A Phase 2 Study of ACR-368 in Endometrial Adenocarcinoma

Inclusion Criteria: General

1. Participant must be able to give signed, written informed consent.

2. Participant must have histologically documented, high-grade endometrial cancer. Arms 1 and 2

3. All high-grade epithelial endometrial histological subtypes are eligibleincluding: endometrioid (all Grade 3), serous, carcinosarcomas, clear-cellcarcinoma, and mixed histologies.Note: Subjects with p53 mutant Grade 2 endometrioid cancer are eligibleArms 3 and 4

4. Serous carcinoma or mixed tumors with a majority component of serous carcinomaor carcinosarcoma where the carcinomatous component is serous carcinoma.

5. Treatment History Requirements: Arms 1 and 2

6. Subject must have received prior platinum-based chemotherapy

7. Subject must have received prior anti-PD-(L)1 therapy

8. Subject must not have received more than three lines of prior systemic therapyArms 3 and 4

9. Subject must have received prior platinum-based chemotherapy

10. Subject must have received prior anti-PD-(L)1 therapy

11. Subject must not have received more than two lines of prior systemic therapy

12. Participant must have histologically confirmed metastatic cancer that has progressedduring or after at least 1 prior therapeutic regimen.

13. Participant must have at least 1 measurable lesion per RECIST v1.1 criteria (bylocal Investigator) in a baseline tumor imaging that has been obtained within 28days of the treatment start. Participant must have radiographic evidence of diseaseprogression based on RECIST v1.1 criteria following the most recent line oftreatment.

14. Arm 1 and 2 only: Participant must be willing to provide tissue from a newlyobtained tumor biopsy from an accessible tumor lesion not previously irradiatedafter written informed consent. Newly obtained is defined as a specimen taken after written informed consent isobtained, during the 28-day Screening period. Note: Subjects at EU sites are not eligible for Arm 1 and Arm 2

15. For all subjects participating in Arm 3 and 4, archival tumor tissue must beprovided either during or after screening either as a tissue block or at least 20unstained slides.

16. Participant must have stabilized or recovered (Grade 1 or baseline) from all priortherapy related toxicities, except as follows:

17. Alopecia is accepted.

18. Endocrine events from prior immunotherapy stabilized at ≤ Grade 2 due to needfor replacement therapy are accepted (including hypothyroidism, diabetesmellitus, or adrenal insufficiency).

19. Neuropathy events from prior cytotoxic therapies stabilized at ≤ Grade 2 areaccepted.

20. Participant must have an Eastern Cooperative Oncology Group Performance Status 0 or

22. Participant must have an estimated life expectancy of longer than 3 months in theclinical judgment of the investigator.

23. Participant must have adequate organ function at Screening, defined as:

24. Absolute neutrophil count > 1500 cells/µL without growth factor support within 2 weeks prior to obtaining the hematology values at Screening.

25. Hemoglobin ≥ 9.0 g/dL.

26. Platelets ≥ 150,000 cells/µL without transfusion within 1 week prior toobtaining the hematology values at Screening.

27. Renal function is defined as Glomerular filtration rate (GFR) ≥ 50mL/min/1.73m2. Note: GFR may be estimated using site standard methods (e.g.,CKD-EPI, MDRD, or Cockcroft-Gault) or measured using 24-hour urine collectionor Chrome-EDTA clearance, as per site standard practice.

28. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upperlimit of normal (ULN); ≤ 5 × ULN if liver metastases are present.

29. Total bilirubin ≤ 1.5 × ULN not associated with Gilbert's syndrome. Ifassociated with Gilbert's syndrome ≤ 3 x ULN is acceptable.

30. Serum albumin ≥ 3 g/dL.

31. Participant must have adequate coagulation profile as defined below if not onanticoagulation. If subject is receiving anticoagulation therapy, then subject mustbe on a stable dose of anticoagulation for ≥ 1 month:

32. Prothrombin time within 1.5 x ULN.

33. Activated partial thromboplastin time within 1.5 x ULN.

Exclusion Criteria: General

1. Participant with known symptomatic brain metastases requiring > 10 mg/day ofprednisolone (or its equivalent). Participants with previously diagnosed brainmetastases are eligible if they have completed their treatment, have recovered fromthe acute effects of radiation therapy or surgery prior to the start of ACR-368treatment, fulfill the steroid requirement for these metastases, and areneurologically stable based on central nervous system imaging ≥ 4 weeks aftertreatment.

2. Participant has mesenchymal tumors of the uterus.

3. Participant has a history of clinically meaningful ascites, defined as history ofparacentesis or thoracentesis with therapeutic intent, within 4 weeks of Screening.Subjects with planned therapeutic paracentesis or thoracentesis between Screeningand Cycle 1 Day 1 dosing are excluded.

4. Participant had systemic therapy or radiation therapy within 3 weeks prior to thefirst dose of study drug.

5. Participants has known human immunodeficiency virus (HIV), hepatitis B, or hepatitisC infection that is considered uncontrolled based on the criteria included inAppendix 2.

6. Participant has a history of clinically meaningful coagulopathy, bleeding diathesis.

7. Participant has cardiovascular disease, defined as:

8. Uncontrolled hypertension defined as blood pressure > 160/90 mmHg at Screeningconfirmed by repeat (medication permitted).

9. History of torsades de pointes, significant Screening electrocardiogram (ECG)abnormalities, including ventricular rhythm disturbances, unstable cardiacarrhythmia requiring medication, pathologic symptomatic bradycardia, leftbundle branch block, second degree atrioventricular (AV) block type II, thirddegree AV block, Grade ≥ 2 bradycardia, uncorrected hypokalemia not amenable tocorrection, congenital long QT syndrome, prolonged QT interval due tomedications, corrected QT based on Fridericia's formula (QTcF) > 450 msec (formen) or > 470 msec (for women).

10. Symptomatic heart failure (per New York Heart Association guidelines; (Caraballo, 2019), unstable angina, myocardial infarction, severecardiovascular disease (ejection fraction < 20%, transient ischemic attack, orcerebrovascular accident within 6 months of Day 1).

11. Participant has a history of major surgery within 4 weeks of Screening.

12. Participant has experienced bowel obstruction related to the current cancer withinthe last 4 weeks or signs or symptoms of intestinal obstruction, which includenausea, vomiting, or objective radiologic finding of bowel obstruction in the last 4weeks before the start of the treatment.

13. Participant has taken a prior cell cycle CHK1 inhibitor, including ACR-368